Discovery of Potent Irreversible Pan-Fibroblast Growth Factor Receptor (FGFR) Inhibitors

Area of Science:

• Oncology
• Medicinal Chemistry
• Drug Discovery

Background:

• Fibroblast Growth Factor Receptors (FGFRs) are implicated in various cancers, making them key therapeutic targets.
• There is a growing interest in developing irreversible inhibitors for enhanced target engagement.
• Selective irreversible FGFR inhibitors are under clinical investigation for cancer treatment.

Purpose of the Study:

• To discover a novel, irreversible pan-FGFR inhibitor using a structure-guided approach.
• To evaluate the in vitro and in vivo efficacy and selectivity of the identified inhibitor.
• To confirm the irreversible binding mechanism of the novel compound.

Main Methods:

• Structure-guided drug design combined with computer-aided simulations.
• In vitro biochemical assays to assess FGFR inhibition and selectivity against VEGFR2.
• In vivo studies using NCI-H1581 and SNU-16 xenograft mouse models.
• Dilution experiments to confirm irreversible target engagement.

Main Results:

• Discovery of a novel irreversible pan-FGFR inhibitor, designated 9g.
• Compound 9g demonstrated superior in vitro inhibitory activity against FGFRs.
• 9g exhibited good selectivity over VEGFR2.
• Significant antitumor activity was observed in NCI-H1581 and SNU-16 xenograft models.
• Irreversible binding of 9g to FGFR was confirmed through dilution studies.

Conclusions:

• The novel irreversible pan-FGFR inhibitor 9g is a promising therapeutic candidate for FGFR-driven cancers.
• The structure-guided and simulation-based approach is effective for discovering targeted irreversible inhibitors.
• Further clinical development of 9g is warranted based on its preclinical efficacy and binding characteristics.